Invasive breast cancer (IBC) is the most diagnosed cancer and the second leading cause of cancer deaths for women in the United States. It is predicted that in the year 2018, about 225,000 women will be diagnosed with IBC and about 40,000 will die from breast cancer (Siegal, et al., A, Cancer Statistics, CA Cancer J. Clin. 68:7-30). Although the mortality rate for breast cancer patients has slightly declined in recent years, it remains very high, mainly due to limited success in curing the cancer after it develops. One rationale for decreasing the mortality rate for breast cancer patients is to identify and treat those patients with high risk developing breast cancer. One cohort recognized to have increased risk for developing breast cancer includes subjects who develop precancerous breast tumors, such as proliferative atypical and non-atypical hyperplasias. For this reason, it would be advantageous to understand the biology of precancerous tumors that have the potential to develop into IBC so that the subjects with precancerous breast tumors at elevated risk can be effectively treated to prevent breast cancer development.
Previous studies have indicated that development of IBC is a multi-step process. Based on animal experiments and epidemiological evidence from humans, it has been proposed that stem cells in terminal duct lobular units undergo proliferation to hyperplasia without atypia, which progress to atypical hyperplasia, then to carcinoma in situ and eventually to IBC (Allred, D. C. et al., Endocrine-Related Cancer, 8:47-61 (2001); Krishnamurthy, et al., Advances in Anatomic Pathology, 9:185-197 (2002)). Several retrospective and prospective studies involving breast biopsies and mastectomy specimens have provided indirect evidence that hyperplastic ducts with and without atypia occur more often in the cancerous breasts than non-cancerous breasts which suggested that hyperplasias are precancerous lesions (Ryan, J. A. et al., Cancer J. Surge, 5:2-8 (1962); Karpus C. M. et al., Ann. Surg, 162:1-8 (1995)). Some retrospective and prospective clinical studies have also established that among the subjects diagnosed with non-cancerous breast tumors, those diagnosed with either atypical hyperplasias or non-atypical hyperplasias have higher risk of developing breast cancer. The relative increased risk of developing breast cancer in a woman with atypical ductal hyperplasia was approximately 5.3 times higher and the risk is two-fold higher for women with non-atypical hyperplasias than those who did not have the above types of tumor growths (Black, M. M. et al., Cancer. 29:338-43 (1972); Dupont, W. D. et al., N. Engl. J. Med. 312:146-51 (1985); Dupont, W. D. et al., Cancer, 71:1258-65 (1993); London, S. J. et al., JAMA, 267:941-4 (1992); Foote, F. W. et al., Annals of Surgery, 121:197-222 (1945); Wellings, S. R. et al., J. Natl. Cancer Inst. 55:231-243 (1975); Allred, D. C. et al., Endocrine-Related Cancer, 8:47-61 (2001); Tavassoli, F. A and Norris, H. J., Cancer, 65:518-29 (1990); Wellings et al., J. Natl. Cancer Inst. 55:231-273 (1975); Page D. L. and Dupont W. D., Breast Cancer Research and Treatment, 28:157-166 (1993); Guray M. and Sahin A. A., Oncologist, 11:435-449 (2006). Taken together, histological and epidemiological evidence points to atypical as well as non-atypical hyperplastic lesions as the earliest precursor lesions that have significantly increased potential for developing IBC.
It is estimated that about 800,000 to 1 million breast biopsies are performed per year in the United States for a suspected tumor or a growth condition, and of these, only about 200,000 to 225,000 turn out to be cancerous; the rest are non-cancerous benign tumors. Among the non-cancerous tumors, about half are true benign and pose little risk. The remaining half of the non-cancerous tumors are proliferative tumors of atypical and non-atypical types. Although not all atypical or non-atypical proliferative lesions progress to IBC, a significant number of women diagnosed with proliferative tumors develop cancer. One study found that approximately 20% of subjects diagnosed with atypical hyperplasias subsequently developed cancer in 1-5 or more years. Among the non-atypical proliferative tumor group that included usual hyperplasias, papillomas and Sclerosing adenosis, approximately 10% developed cancer in 1-5 or more years (Hartman et al., New England J. Med, 353: 229-237 (2005)). Follow up studies estimated that of the approximately 300,000-400,000 proliferative tumors diagnosed every year in the United States, approximately 40,000 develop into IBC after 1-5 or more years (Worsham et al., Breast J., 13:116-121 (2007); Coopey et al., Breast Cancer Res. And Treatment, 10549-012, 2318(2012)). Therefore, it would be advantageous to stratify the approximately 40,000 subjects who will progress to cancer and target them for prophylactic treatments to prevent breast cancer from developing.
Thus, there is a need for improved materials and method for assessing early hyperplastic lesions, the presence of which in a subject is a significant indicator that a subject will eventually develop invasive breast cancer. Embodiments of the present disclosure described herein provide such improvements.